1. Field of the Invention
The present invention relates to novel crystalline forms of (R)-3-[N-(3′-chlorobiphenyl-4-ylmethyl)-N′-(3-hydroxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid isopropyl ester, which are metabolized in vivo to a compound having activity as a neprilysin inhibitor. The invention also relates to pharmaceutical compositions comprising such compound, processes and intermediates for preparing such compound and methods of using the compound to treat diseases such as hypertension, heart failure, pulmonary hypertension, and renal disease.
2. State of the Art
Commonly-assigned U.S. Patent Publication No. 2012/0157386 to Smith et al., filed on Dec. 14, 2011, discloses novel compounds that have activity as neprilysin inhibitors, the disclosure of which is incorporated herein by reference. In particular, the compound, (R)-3-[N-(3′-chlorobiphenyl-4-ylmethyl)-N′-(3-hydroxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid isopropyl ester is specifically disclosed in this application.
The chemical structure of (R)-3-[N-(3′-chlorobiphenyl-4-ylmethyl)-N′-(3-hydroxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid isopropyl ester is represented by formula I:

When preparing compounds for long term storage and when preparing pharmaceutical compositions and formulations, it is often desirable to have a crystalline form of the therapeutic agent that is neither hygroscopic nor deliquescent. It is also advantageous to have a crystalline form that has a relatively high melting point (i.e., greater than about 100° C.), which allows the material to be processed, for example, micronized, without significant decomposition. Accordingly, a need exists for a stable, non-deliquescent form of (R)-3-[N-(3′-chlorobiphenyl-4-ylmethyl)-N′-(3-hydroxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid isopropyl ester, which has an acceptable level of hygroscopicity and a relatively high melting point.